Loh, J. T., Teo, J. K. H., Kannan, S., Verma, C. S., Andiappan, A. K., Lim, H.-H., & Lam, K.-P. (2023). DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11. Science Signaling, 16(809). https://doi.org/10.1126/scisignal.adg5171
Abstract:
The scaffolding protein CARD11 is a critical mediator of antigen receptor signaling in lymphocytes. Hypomorphic (partial loss-of-function) mutations in CARD11 are associated with the development of severe atopic dermatitis, in which T cell receptor signaling is reduced and helper T cell differentiation is skewed to an allergy-associated type 2 phenotype. Here, we found that the docking protein DOK3 plays a key role in the pathogenesis of atopic dermatitis by suppressing CARD11 activity. DOK3 interacted with CARD11 and decreased its phosphorylation in T cells by recruiting the catalytic subunit of protein phosphatase 4, thereby dampening downstream signaling. Knocking out
Dok3
enhanced the production of the cytokine IFN-γ by T cells, which conferred protection against experimental atopic dermatitis–like skin inflammation in mice. The expression of
DOK3
was increased in T cells isolated from patients with atopic dermatitis and inversely correlated with
IFNG
expression. A subset of hypomorphic CARD11 variants found in patients with atopic dermatitis bound more strongly than wild-type CARD11 to DOK3. Our findings suggest that the strength of the interaction of DOK3 with CARD11 may predispose individuals to developing atopic dermatitis.
License type:
Publisher Copyright
Funding Info:
This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : NMRC/OFIRG19may-0083
This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : NMRC/OFYIRG21nov-0035
This research / project is supported by the A*STAR - Career Development Award
Grant Reference no. : 202D800012
Description:
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on Vol 16, Issue 809
and 31 Oct 2023, doi.org/10.1126/scisignal.adg5171